The Skin Immune System Pt. 1

What regions of the skin are potentially portals of entry for pathogens?

• Epidermis

• Adnexa (Hair follicles and supporting glands)

• Dermis and panniculus/subcutis

• Extension from underlying tissues

In what ways can substances enter into the epidermis of the skin?

• Absorption

• e.g. Lipophilic drugs

• Direct contact

• e.g. Caustic chemicals

• Colonisation

• e.g. Dermatophytes (ringworm)

• Penetration

• e.g. Hookworm larvae; trauma inc. UV radiation

• Impaired barrier

• Micro-organisms

• Allergens

In what ways can substances enter into the adnexa of the skin?

• Entry via follicle ostium

• Ostium = tiny surface openings are part of the skin structure that allows microparticles to pass through the epidermis

• Rupture of follicle or adnexal glands (Called Furunculosis)

• If immune system exposed to hair follicles → causes nasty reaction and inflammation

In what ways can substances enter into the dermis/panniculus of the skin?

By tracking along “something”, such as:

• Blood vessels

• Drugs, toxins, emboli, leukocyte trafficking

• Nerves (rare)

• e.g. Feline herpesvirus 1

• Axonal flow along sensory nerves causes dermatitis

In what ways can substances enter into the underlying tissues of the skin?

• Penetration by damaged bone

• Fracture trauma

• Extension from adjacent tissues

• Tumour or infection from lymph node, gland, muscle or bone

How does the skin (in general) respond to inflammation and injury?

• Most conditions provoke an inflammatory reaction

• The skin is limited in how it can respond

• And there are a number of typical primary and secondary lesion patterns

• Primary → caused directly by insult

• Secondary → caused by animal responding to insult, like raw skin resulting from itching

• Also, several overlapping processes may occur together

How can we characterize patterns of skin disease?

Epidemiology

• Breed, sex, location, season

Clinical Presentation

• Macroscopic lesions, distribution, configuration

Histopathology

• Pattern analysis

• Postgraduate!

When considering epidemiology, what should you consider regarding skin conditions in the following:

• Breed

• Skin fold dermatitis (intertrigo) in Sharpei, Bulldog, Pekinese, pug

• Sex

• Symmetrical alopecia with oestrogen production by Sertoli cell tumour in male dogs

• Location

• Cutaneous haemangiosarcoma following sun exposure in dogs in Grenada, West Indies

• Season

• Flea allergy dermatitis

• More common in temperate climates but seasonal in colder climates

Describe the factors used to describe the clinical presentation of skin diseases.

• Clinical signs = macroscopic pathology (What is seen in practice is also seen by pathologists)

• Distribution:

• Where are the lesions on the body?

• Description:

• Size, shape, colour, consistency

• Gives clues as to the lesion type

  • Red: inflammatory

  • Thickened: hyperplastic

  • Bald: alopecic / hypotrichoic

  • Nodular: Inflammatory / neoplastic

How are histopathology patterns named?

A pattern consists of two parts: a component of the skin (e.g. epidermis) and a histologic reaction of that component to injury (e.g. hyperkeratosis) = pattern (e.g. epidermal hyperkeratosis)

How do primary skin lesions develop?

• List some of the main examples.

• Develop spontaneously as a result of underlying disease

• Useful in trying to determine aetiology and pathogenesis of disease

• Examples

• Macule or (>1cm) Patch

• Papule or (>1cm) Plaque

• Vesicle or (>1cm) Bulla

• Pustule (or Abscess)

• Wheal (or Hive)

• Cyst

• Nodule

What is a “macule”?

• primary skin lesion

• A circumscribed, non-palpable spot characterised by a change in the colour of the skin.

• A larger lesion >1.0 cm is a patch.

• e.g. haemorrhage, lentigo

Describe the passive defenses present in the skin.

Creates a physical barrier.

• Hair, hooves and claws

• Thermal insulation AND dissipation

• Mechanical protection

• Sensory function

• Melanocytes

• Cap of pigment = photoprotection

• Epidermal barrier — more later!

• Skin surface lipids

• Stratum corneum

• Basement membrane

• Dermis and superficial dermal fat

Describe the active host defense in the skin. 

• Skin immune system

• Innate immunity

• Immediate, non-specific

• Adaptive immunity

• Delayed but targeted

Reminder** what is the difference between innate and adaptive immunity?

How does the innate immune system respond to insult in the skin?

• Exposure to antigen, recognized by langerhans’ cells and the keratinocytes

• Release of primary cytokines

• Promote inflammation

• Upregulation of endothelial expression of adhesion molecules

• Recruitment of additional innate effector cells

• Activation of skin cells & resident innate immune cells

  • Endothelial cells become activated, expressing attachment sites for immune system

• Neutrophils, macrophages, NK cells

• Langerhans' and dermal dendritic cells carry antigen to draining lymph node

• Dendritic cells carry the antigens to the T-cells, making the bridge between the innate and adaptive response

How does the adaptive immune response become activated?

• Memory T cells carry T cell receptors (TCRs) specific for antigen previously encountered in skin

• Interaction of antigen specific T cells with APCS results in T cell activation

• Cytokines also stimulate expression of T cell specific chemokine ligands on endothelium

• T cells recruited by antigen non-specific mechanism

Summarize the difference in the important cells and effector mechanisms between innate and adaptive immunity. 

What makes up the skin barrier?

• The physical and permeability barrier is regenerated by the process of keratinisation

• Proliferation, differentiation, cell death

What are key features of the stratum corneum?

• Lipid bilayer of cell membranes = cornified envelope, each keratinocyte is joined together by corneodesmosomes

• Loricrin and involucrin

• Filaggrin

• Control of desquamation

• By the balance of stratum corneum protease inhibitors & proteases (Healthy smooth normal skin, or you could have flaky skin or ulceration, both abnormal balance)

• Skin pH

  • Dog normal 5.5-7.5

Reminder** Summarize each layer of the skin and the primary processes happening in each of those layers. 

What is the purpose of cutaneous lipids?

• How much is found within the skin?

• Healthy stratum corneum is up to 85% lipid

• Sphingolipids (ceramide)

• Cholesterol

• Free fatty acids

• Sphingolipids and fatty acids important for...

• Physical barrier

• Permeability barrier and

• Immunologic barrier

• Some molecules have ANTIMICROBIAL properties

• e. g. Sphingoid bases derived from epithelial sphingolipids

• Mechanisms are not fully understood

What cells produce antimicrobial peptides and what do they do?

• Produced by neutrophils, macrophages, epithelial cells (etc)

• Activate and recruit inflammatory cells & alarm and arm keratinocytes

How does AMP expression look like in normal skin?

• What does it look like in injured skin?

• Normally skin has a normal low level of AMP production

• Injured keratinocytes increase AMP production

  • Neutrophil and mast cell recruitment

  • Inflammatory cells also produce AMPs (Producing a compounding effect)

  • AMPs stimulates angiogenesis and keratinocyte proliferation leading to thickening of the skin

What is atopic dermatitis?

• Describe what causes it and classic lesions for the condition.

• Classic lesions: reddening and alopecia

  • Ulceration due to itching by animal

• Allergens can be absorbed via the skin +/- inhaled

• Causes inflammation, oedema and mast cell rich infiltrate

• Abnormal canine skin barrier

• Variations in filaggrin expression

  • Geographic and breed variations

  • Downregulation (but not gene mutation) of filaggrin reported in WHWTs

• Disorganised lipid lamellae

• Altered ratio of cholesterol / ceramides

• Altered balance of antimicrobial peptides

Why are dust mites and normal bacteria associated with atopic dermatitis?

• Exogenous producers of proteases which create gaps in skin, allowing allergens to enter the skin 

What is the importance of the skin’s microbiome?

• The skin, like the gut, needs microbial signals for proper immune function

• Reciprocal: the cutaneous and innate immune responses modulate skin microbiota AND the microbiota modulate the immune system

• Diverse and variable population of commensal microbes e.g. Staph. epidermidis

What factors affect the skin microbiome?

How does the microbiome and innate immune response modulate skin microbiota?

• For example: Staphylococcus epidermidis (commensal) produces

• Antimicrobial peptides

• e.g. Modulins: act as barrier to pathogenic colonisation

• Small molecules

• Which enhance expression of defensins via Toll-like receptors (TLRs)

What are the main cellular components of the skin?

• Endothelial cells

• Express adhesion molecules and bind T lymphocytes

• Keratinocytes

• Roles in defence and immune modulation

• Dendritic/Langerhans cells

• Major role in antigen presentation

  • Epidermal (Langerhans cells) and dermal

• Mast cells

• Release histamine etc.

• Lymphocytes

• T cells

• B cells

Reminder** Cells of the immune system.

• Myeloid Lineage

• Lymphoid Lineage

How are keratinocytes involved in the immune response?

• Act as sentinel cells

• Express Pattern Recognition Receptors (PRRs)

• Respond to DAMPs (e.g. generated by UV light) and PAMPs (associated with microbial invasion)

• Induce innate immune response

• Effect is po-inflammatory

• Produce a complex mixture of AMPs, pro-inflammatory cytokines and chemokines

• Non-professional antigen-presenting cell

• Expresses MHC class Il molecules

• Can interact with antigen-experienced T cells

• Mechanism through which the skin discriminates between commensal and harmful bacteria is unclear - tolerance?

What are DAMPs and PAMPs?

DAMP: damage associated molecular pattern

PAMP: pathogen associated molecular pattern

How to keratinocytes in the innate immune system protect the body?

• Provide a physical barrier

• Make antimicrobial peptides which activate mast cells and help kill pathogens

• Also recruit inflammatory cells

• Can present pathogens to memory T-cells

What are the main roles of the Langerhans cells?

• Aka Epidermal Dendritic Cells

• Dendritic cells link the innate and adaptive immune responses

• Langerhans cells interact with skin resident memory T cells

• Help maintain a balance between immune reactions and tolerance

  • If too tolerant of “self” - pathogen becomes overgrown

  • If launching an immune response to something that is self → hypersensitivty